Compounds that stimulate glucose utilization and methods of use

ABSTRACT

The invention provides novel compounds of the Formula (I) that stimulate rates of glucose oxidation in myocardial cells. The invention also relates to pharmaceutical compositions comprising compounds capable of stimulation of glucose oxidation, methods for increasing glucose oxidation rates in myocardial cells, and methods of treatment of myocardial ischemia 
                         
wherein
         W is C 1 –C 6  alkyl, halogen, or aryl;   Cyc is C 3  or C 4  cycloalkyl;   p is 0–3 for Cyc being C 4  cycloalkyl and p=0–2 for Cyc being C 3  cycloalkyl;   Y is O, S, or NR, where R═H, alkyl or aryl;   X is O, S, NR, or CR 3 R 4 ;   Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl;   R 1  is H, alkyl, aryl or O;   R 2  is H, alkyl or aryl;   R 3  and R 4  are, independently, H, alkyl or aryl; and   n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.

This application is a 371 of PCT/IB02/02525, filed Apr. 1, 2002 andclaims priority to U.S. Provisional Application No. 60/280,616, filedMar. 30, 2001,

FIELD OF THE INVENTION

The invention relates to novel compounds that stimulate rates of glucoseoxidation in myocardial cells. The invention also relates topharmaceutical compositions comprising compounds capable of stimulationof glucose oxidation, methods for increasing glucose oxidation rates inmyocardial cells, and methods of treatment of myocardial ischemia.

BACKGROUND OF THE INVENTION

Myocardial ischemia is a common clinical pathology that occurs in thesetting of angina pectoris, acute myocardial infarction, or duringcardiac surgery. Myocardial ischemia is a major clinical problem, withits complications being the major cause of mortality and morbidity inWestern society.

It has been shown that stimulating glucose oxidation both during andfollowing ischemia can benefit the ischemic heart. Br J Pharmacol 128:197–205, 1999, Am J Physiol 275: H1533–41, 1998. Biochimica etBiophysica Acta 1225: 191–9, 1994, Pediatric Research 34: 735–41, 1993,Journal of Biological Chemistry 270: 17513–20, 1995. Biochimica etBiophysica Acta 1301: 67–75, 1996, Am J Cardiol 80: 11A–16A, 1997,Molecular & Cellular Biochemistry 88: 175–9, 1989, Circ Res 65: 378–87,1989, Circ Res 66: 546–53, 1990, American Journal of Physiology 259:H1079–85, 1990, American Journal of Physiology 261: H1053–9, 1991, Am JPhysiol Heart Circ Physiol 280: H1762–9., 2001, J Am Coll Cardiol 36:1378–85., 2000.

To meet the high energy demands of the contracting muscle, the heartmust produce a constant and plentiful supply of the free energy carrier,adenosine triphosphate (ATP). This energy is produced by the metabolismof a variety of carbon substrates, including carbohydrates such asglucose. The metabolism of fatty acid is the other major source ofenergy for the heart.

Glucose metabolism in the heart consists of two important pathways,namely glycolysis and glucose oxidation.

It has been shown that during ischemia (such as that produced by anginapectoris, myocardial infarction or heart surgery) the levels ofcirculating fatty acids in the plasma can be dramatically elevated. AmHeart J 128: 61–7, 1994.

As a result, during ischemia and reperfusion the heart is exposed tohigh levels of fatty acids, which results in the preferential use offatty acids as an oxidative substrate over glucose. It further has beenshown that this over-reliance on fatty acids as a major source of ATPcontributes to fatty acid-induced ischemic damage. This observation hassparked numerous approaches directed at switching substrate utilizationback to glucose in an attempt to protect the heart from fattyacid-induced ischemic damage. J Cardiovasc Pharmacol 31: 336–44., 1998,Am Heart J 134: 841–55., 1997, Am J Physiol 273: H2170–7., 1997,Cardiovasc Drugs Ther 14: 615–23., 2000, Cardiovasc Res 39: 381–92.,1998, Am Heart J 139: S115–9., 2000, Coron Artery Dis 12: S8–11., 2001,Am J Cardiol 82: 14K–17K., 1998, Molecular & Cellular Biochemistry 172:137–47, 1997, Circulation 95: 313–5., 1997, Gen Pharmacol 30: 639–45.,1998, Am J Cardiol 82: 42K–49K., 1998, Coron Artery Dis 12: S29–33.,2001, Coron Artery Dis 12: S3–7., 2001, J Nucl Med 38: 1515–21., 1997.Current approaches that are used to manipulate myocardial energymetabolism involve either stimulating glucose metabolism directly orindirectly (i.e., inhibiting fatty acid metabolism).

Since high fatty acid oxidation rates markedly decrease glucoseoxidation, one approach to increasing glucose oxidation is to inhibitfatty acid oxidation. This has proven effective both during andfollowing ischemia, and this pharmacological approach is starting to seeclinical use. Although a number of pharmacological agents designed toinhibit fatty acid oxidation have recently been developed, the directβ-oxidation inhibitor, trimetazidine, was the first anti-anginal agentwidely used that has a mechanism of action that can be attributed to anoptimization of energy metabolism Circulation Research. 86: 580–8, 2000.

Trimetazidine primarily acts by inhibiting fatty acid oxidation, therebystimulating glucose oxidation in the heart.

A second clinically effective agent that switches energy metabolism fromfatty acid to glucose oxidation is ranolazine. It has been shown thatthis agent stimulates glucose oxidation secondary to an inhibition offatty acid oxidation Circulation 93: 135–42., 1996.

The detrimental effects of fatty acids on mechanical function during andfollowing ischemia are also attenuated by agents that increase glucoseoxidation directly. Numerous experimental studies have demonstrated thatstimulation of glucose oxidation by using dichloroacetate (DCA)following ischemia (at the expense of fatty acids) can benefit theischemic heart. Am Heart J 134: 841–55, 1997. Although DCA is aneffective compound designed to stimulate glucose oxidation, it has ashort biological half-life.

Therefore, there is need to develop novel class of compounds and toidentify compounds that can stimulate glucose oxidation, have longbiological life, and be effective in treatment or prevention ofmyocardial ischemia

SUMMARY OF THE INVENTION

The invention is directed to novel compounds represented by the Formula(I):

wherein

-   -   W is C₁–C₆ alkyl, halogen, or aryl;    -   Cyc is C₃ or C₄ cycloalkyl;    -   p is 0 to 3;    -   Y is O, S, or NR, where R═H, alkyl or aryl;    -   X is O, S, NR, or CR³R⁴;    -   Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl;    -   R¹ is H, alkyl or aryl;    -   R₂ is H, alkyl, aryl or O;    -   R³ and R⁴ are, independently, H, alkyl or aryl; and    -   n is an integer from 1 to 10; or a pharmaceutically acceptable        salt, ester or prodrug thereof.

The invention is further directed to methods for increasing or improvingglucose utilization in myocardial or other types of cells, tissue ororgans of warm blooded animals, especially those which are capable ofhigh glucose metabolism (e.g., heart and other muscles). The methodcomprises treating cells, tissue or organs with substituted orunsubstituted cyclopropane carboxylic acid or cyclobutane carboxylicacid represented by the Formula (II) or their derivative compoundsaccording to Formula (I).

wherein W, Cyc and p are as defined above.

The invention if also directed to pharmaceutical compositions comprisingcompounds according to the Formula (I) and suitable pharmaceuticalcarriers, excipients or fillers.

The invention is further directed to a method of treatment ofphysiological conditions or disorders known to be effectively treated byincreasing of cell glucose utilization. The method comprisesadministering to patients in need of such treatment effective amounts ofpharmaceutical compositions comprising substituted or unsubstitutedcyclopropane carboxylic acid or cyclobutane carboxylic acid according toFormula (II) or their derivative compounds according to the Formula (I).

The invention is further directed to kits including the pharmaceuticalcompositions according to the invention.

Invention methods are applicable for treating any warm blooded animalsubjects, such as mammals, e.g., humans, primates, etc.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows glucose oxidation in an isolated perfused working rat heartmodel with the indicated concentrations of cyclopropanecarboxylic acid,2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester (MM054).

FIG. 2 shows glucose oxidation in an isolated perfused working rat heartmodel with the indicated concentrations of cyclobutanecarboxylic acid,2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester (MM056).

FIG. 3 shows glucose oxidation in an isolated perfused working rat heartmodel with increasing concentrations of cyclopropanecarboxylic acid,2-isopropoxy-ethyl ester (MM070).

FIG. 4 shows glucose oxidation in an isolated perfused working rat heartmodel with increasing concentrations of cyclopropanecarboxylic acid(MM001).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel compounds based on cyclopropanecarboxylic acid or cyclobutane carboxylic acid. The compounds exhibitglucose oxidation stimulating activity in myocardial cells and othertypes of cells. The compounds according to the present invention arerepresented by the Formula (I):

wherein

-   -   W is C₁–C₆ alkyl halogen, or aryl;    -   Cyc is C₃ or C₄ cycloalkyl;    -   p is 0–3 when Cyc is C₄ cycloalkyl, and p is 0–2 when Cyc is C₃        cycloalkyl;    -   Y is O, S, or NR , where R═H, alkyl or aryl;    -   X is O, S, NR, or CR³R⁴;    -   Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkyl carbonyl;    -   R¹ is H, alkyl or aryl;    -   R² is H, alkyl, aryl or O;    -   R³ and R⁴ are, independently, H, alkyl or aryl and    -   n is an integer from 1 to 10; or a pharmaceutically acceptable        salt, ester or prodrug thereof.

As used herein, the term “alkyl” means straight or branched alkanechain, which may be, optionally substituted with, for example, halogens,cyclic or aromatic substituents.

As used herein, the terms “aryl” or “aromatic” refer to mono- andbi-cyclic structures comprising 5–12 carbon atoms, preferably monocyclicrings containing six carbon atoms. The ring may be optionallysubstituted with alkyl, alkeny, halogen, alkoxy, or haloalkylsubstituents.

The compounds according to the present invention can be obtained fromsubstituted or unsubstituted cyclopropane carbonyl chloride orcyclobutane carbonyl chloride according to the following reactionscheme:

or their substituted derivatives and

where R1, R2, Y, X, Z and n are as defined above.

Preferred solvent is dichloromethane and preferred base catalysts aretriethylamine and pyridine.

Reaction conditions may be varied depending on the starting materialsand the desired end product. Optimization of the reaction conditionswould be apparent for one of ordinary skill.

Preferred compounds have unsubstituted cycloalkyl rings.

In the preferred embodiments Y is O, and X is N or O, n is 1–4, p is 0,R¹, R², R³ and R⁴ are hydrogens, and Z is lower alkyl, cycloalkyl orphenyl; or Y is N, and X is O, n is 1 or 2, p is 0, R¹, R², R³ and R⁴are hydrogens, and Z is hydrogen.

The compounds according to the present invention can be exemplified bythe following compounds:

-   -cyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl    ester;-   -cyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl    ester;-   -(cyclobutanecarbonyl-amino)-acetic acid;-   -cyclopropanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester;-   -2-(cyclopropanecarbonyl-amino)-propionic acid;-   -cyclobutanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester;-   -cyclobutanecarboxylic acid, 2-(2-butoxy-ethoxy)-ethyl ester;-   -cyclobutanecarboxylic acid, 2-(2-ethoxy-ethoxy)-ethyl ester;-   -cyclopropanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester;-   -cyclobutanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester;-   -cyclopropanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethoxy)-ethyl    ester;-   -cyclobutanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester;-   -cyclopropanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;-   -cyclobutanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;-   -cyclopropanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;-   -cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;-   -cyclopropanecarboxylic acid 2-isopropoxy-ethyl ester;-   -cyclobutanecarboxylic acid 2-isopropoxy-ethyl ester;-   -cyclopropanecarboxylic acid,    2-(2-cyclobutanecarbonyloxy-ethoxy)-ethyl ester;-   -cyclopropanecarboxylic acid,    2-[2-(2-cyclopropanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester; and-   -cyclobutanecarboxylic acid,    2-[2-(2-cyclobutanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester.

The invention further provides a method for increasing the rate ofglucose oxidation and improving glucose utilization in myocardial andother cells, tissue or organs of humans and animals. It has beendiscovered that substituted or unsubstituted cyclopropanecarboxylicacid, cyclopropanecarboxylic acid represented by the Formula (II) andcyclobutanecarboxylic acid derivatives, such as cyclopropanecarboxylicacid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester andcyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl esterand other compounds represented by the Formula (I) can increase glucoseutilization in myocardial an other types of cells, tissue or organs ofwarm blooded animals, including humans.

wherein W is C₁–C₆alkyl, halogen, or aryl;

-   -   Cyc is C₃ or C₄ cycloalkyl; and    -   p is 0–3 when Cyc is C₄ cycloalkyl, or p is 0–2 when Cyc is C₃        cycloalkyl;

The method according to the present invention comprises treating cells,tissue or organs of the animal with at least one compound represented byFormula (I) or Formula (II). The compounds of the Formula (I) or Formula(II) can be delivered to the cells, tissues or organs by oraladministration, injection or infusion, etc., of the compounds of theFormula (I) or (II) to the animals.

The invention further provides pharmaceutical compositions comprising,as its active component, at least one compound according to the Formulas(I) or (II), their pharmaceutically acceptable salt, ester or prodrugs.Pharmaceutical compositions comprising more than one compound accordingto the Formulas (I) or (II), their various mixtures and combinations arealso within the scope of the present invention.

Pharmaceutical compositions or formulations include carriers andexcipients compatible with oral, intravenous, intramuscular,intraarterial, intracranial, and intracavity administration.Pharmaceutical formulations further include colloidal dispersionsystems, or lipid formulations (e.g., cationic or anionic lipids),micelles, microbeads, etc.

Pharmaceutical compositions of the invention include pharmaceuticallyacceptable and physiologically acceptable carriers, diluents orexcipients. Examples of suitable carriers, diluents and excipientsinclude solvents (aqueous or non-aqueous), solutions, emulsions,dispersion media, coatings, isotonic and absorption promoting ordelaying agents, compatible with pharmaceutical administration, andother commonly used carriers known in the art.

Compositions can also include carriers to protect the compositionagainst rapid degradation or elimination from the body, such as acontrolled release formulation, including implants and microencapsulateddelivery systems. For example, a time delay material such as glycerylmonostearate or glyceryl stearate alone, or in combination with a wax,may be employed.

Pharmaceutical compositions can be formulated to be compatible with aparticular route of administration. For oral administration, acomposition can be incorporated with excipients and used in the form oftablets, pills or capsules, e.g., gelatin capsules. Pharmaceuticallycompatible binding agents, and/or adjuvant materials can be included inoral formulations. The tablets, pills, capsules, etc., can contain anyof the following ingredients, or similar compounds: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; or a flavoring orsweetening agent.

Pharmaceutical compositions for parenteral, intradermal, or subcutaneousadministration can include a sterile diluent, such as water, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; antibacterial agents such as benzyl alcoholor methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose.

Pharmaceutical compositions for injection include sterile aqueoussolutions (where water-soluble) or dispersions and sterile powders forthe extemporaneous preparation of sterile injectable solutions ordispersion. For intravenous administration, suitable carriers includephysiological saline, bacteriostatic water, Cremophor EL™ (BASF,Parsippany, N.J.) or phosphate buffered saline (PBS). Antibacterial andantifungal agents include, for example, parabens, chlorobutanol, phenol,ascorbic acid and thimerosal. Isotonic agents, for example, sugars,polyalcohols such as manitol, sorbitol, sodium chloride may be includedin the composition. Including an agent which delays absorption, forexample, aluminum monostearate and gelatin can prolong absorption ofinjectable compositions.

The pharmaceutical formulations can be packaged in dosage unit form forease of administration and uniformity of dosage. Dosage unit form asused herein refers to physically discrete units suited as unitarydosages for the subject to be treated; each unit containing apredetermined quantity of active compound calculated to produce thedesired therapeutic effect in association with the pharmaceuticalcarrier or excipient.

The compositions can be administered by any route compatible with adesired outcome. Thus, routes of administration include oral (e.g.,ingestion or inhalation), intraperitoneal, intradermal, subcutaneous,intravenous, intraarterial, intracavity, intracranial, and parenteral.The compositions can also be administered using implants andmicroencapsulated delivery systems.

Compositions, including pharmaceutical formulations can further includeparticles or a polymeric substance, such as polyesters, polyamine acids,hydrogel, polyvinyl pyrrolidone, ethylene-vinylacetate, methylcellulose,carboxymethylcellulose, protamine sulfate, or lactide/glycolidecopolymers, polylactide/glycolide copolymers, or ethylenevinylacetatecopolymers. Cyclopropanecarboxylic acid, cyclopropanecarboxylic acid andderivatives and modified forms thereof can be entrapped inmicrocapsules, for example, by the use of hydroxymethylcellulose orgelatin-microcapsules, or poly (methylmethacrolate) microcapsules,respectively, or in a colloid drug delivery system.

In instances where cell, tissue or organ targeting is desired, acomposition of the invention can of course be delivered to the targetcell, organ or tissue by injection or infusion or the like. Targetingcan be achieved by injection or infusion in practicing the methods ofthe invention. Targeting can also be achieved by using proteins thatbind to a cell surface protein (e.g., receptor or matrix protein)present on the cell or population of cell types. For example, antibodiesor antibody fragments (e.g., Fab region) that bind to a cell surfaceprotein can be included in the delivery systems in order to facilitatecell, tissue or organ targeting. Viral coat proteins that bindparticular cell surface proteins can be used for targeting. For example,naturally occurring or synthetic (e.g. recombinant) retroviral envelopeproteins with known cell surface protein binding specificity can beemployed in the liposomes in order to intracytoplasmically delivercyclopropanecarboxylic acid, cyclopropanecarboxylic acid and derivativesand modified forms thereof into target cells, tissue or organs. Thus,delivery vehicles, including colloidal dispersion systems, can be madeto have a protein coat in order to facilitate targeting orintracytoplasmic delivery of cyclopropanecarboxylic acid,cyclopropanecarboxylic acid and derivatives and modified forms thereof.

The invention further provides a method for prophylactic and therapeutictreatments of various physiological condition or disorder treatable byincreasing or improving glucose utilization in cells, tissue or organsof a patient by administering to the patient in need of such treatment,effective amounts of pharmaceutical compositions comprising substitutedor unsubstituted cyclopropanecarboxylic acid, cyclopropanecarboxylicacid and cyclobutanecarboxylic acid derivative compounds represented bythe Formulas (I) and (II).

Disorders or conditions that can be treated with a method according tothe present invention include, for example, ischemic/reperfusion injury,post myocardial infarction, angina, heart failure, a cardiomyopathy,peripheral vascular disease, diabetes, and lactic acidosis, or symptomsor side effects associated with heart surgery (e.g., open heart surgery,bypass surgery, heart transplant).

The method according to the present invention includes administering apharmaceutical compositions comprising effective amounts of substitutedor unsubstituted cyclopropanecarboxylic acid, cyclopropanecarboxylicacid and cyclobutanecarboxylic acid derivative compounds represented bythe Formulas (I) and (II) in a single daily dose, or the total dailydosage may be administered in divided doses several times daily.Furthermore, the pharmaceutical compositions may be administered as asingle dose or over a period of time.

Patients that can be treated with the method according to the presentinvention include all known kind of mammals, including non humanprimates (apes, gibbons, chimpanzees, orangutans, macaques), companionanimals (dogs and cats), farm animals (horses, cows, goats, sheep,pigs), experimental animals (mouse, rat, rabbit, guinea pig), andhumans.

The dosage regiment utilizing the pharmaceutical compositions accordingto the present invention is selected based on various factors such astype of physiological condition to be treated, age, weight, sex of thepatient, severity of the conditions to be treated, the route ofadministration, and particular compound contained in the pharmaceuticalcomposition. A physician or veterinarian of ordinary skill can readilydetermine and prescribed the effective amount of the pharmaceuticalcomposition to prevent or to treat the specific physiological condition.

The daily dosage may be varied over wide range and can be such that theamount of the active compound selected from substituted or unsubstitutedcyclopropanecarboxylic acid, cyclopropanecarboxylic acid andcyclobutanecarboxylic acid derivative compounds represented by theFormulas (I) and/or Formula (II) is sufficient to increase glucoseutilizationin a cell, tissue or organ of a warm blooded animal and toachieve the desired effect of alleviating or preventing fattyacid-induced ischemic damage.

The invention provides kits containing substituted or unsubstitutedcyclopropanecarboxylic acid, cyclopropanecarboxylic acid and derivativesand modified forms thereof represented by the Formulas (I) and Formula(II), including pharmaceutical formulations, packaged into a suitableset. A kit typically includes a label or packaging insert includinginstructions for use, in vitro, in vivo, or ex vivo, of the componentstherein.

The term “packaging material” refers to a physical structure housing thecomponents of the kit, such as cyclopropanecarboxylic acid,cyclopropanecarboxylic acid or derivatives or modified forms thereof.The packaging material can maintain the components sterilely, and can bemade of material commonly used for such purposes (e.g., paper,corrugated fiber, glass, plastic, foil, ampules, etc.). The label orpackaging insert can include appropriate written instructions, forexample, practicing a method of the invention.

Kits of the invention therefore can additionally include instructionsfor using the kit components in a method of the invention. Instructionscan include instructions for practicing any of the methods of theinvention described herein. Thus, for example, a kit can include acyclopropanecarboxylic acid, cyclopropanecarboxylic acid or a derivativeor modified form thereof in a pharmaceutical formulation in a container,pack, or dispenser together with instructions for administration to ahuman subject. Instructions may additionally include indications of asatisfactory clinical endpoint or any adverse symptoms that may occur,or any additional information required by the Food and DrugAdministration for use in humans.

A kit may include instructions for increasing or improving glucoseutilization in vitro, ex vivo or in vivo. In other embodiments, a kitincludes instructions for treating a disorder associated with deficientor inefficient glucose utilization. In one aspect, the instructionscomprise instructions for treating a subject having or at risk of havingischemic/reperfusion injury, post myocardial infarction, angina, heartfailure, a cardiomyopathy, peripheral vascular disease, diabetes, orlactic acidosis. In another aspect, the instructions compriseinstructions for treating a subject having or at risk of having heartsurgery (e.g., open heart surgery, bypass surgery, heart transplant andangioplasty).

The instructions may be on “printed matter,” e.g., on paper or cardboardwithin the kit, or on a label affixed to the kit or packaging material,or attached to a vial or tube containing a component of the kit.Instructions may additionally be included on a computer readable medium,such as a disk (floppy diskette or hard disk), optical CD such as CD- orDVD-ROM/RAM, magnetic tape, electrical storage media such as RAM and ROMand hybrids of these such as magnetic/optical storage media.

Kits can additionally include a buffering agent, a preservative, or astabilizing agent. Each component of the kit can be enclosed within anindividual container and all of the various containers can be within asingle package.

The present invention is further illustrated in the following exampleswherein all parts, percentages, and ratios are in equivalents, alltemperatures are in ° C., and all pressures are atmospheric unlessotherwise indicated:

EXAMPLE 1

Preparation of Cyclopropanecarboxylic Acid,2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl Ester

Triethylene glycol monomethyl ether (1.1 eq, 5.26 mmol, 0.84 ml),triethylamine (1.1 eq, 5.26 mmol, 0.73 ml) was taken in a 10 ml roundbottom flask and dichloromethane (3 ml) was added. This mixture wascooled to 0° C. and then cyclopropanecarbonyl chloride (4.78 mmol, 0.5g, 0.43 ml) was added in a dropwise fashion maintaining the temperatureat 0° C. with constant stirring.A yellowish-orange solid was observed after some time. Stirring wascontinued for 1 hr at 0° C. The reaction was monitored by thin layerchromatography, and then quenched with saturated ammonium chloridesolution. It was then transferred to a separatory funnel, washed with 5%sodium bicarbonate (2×5 ml), 1:1 hydrochloric acid (2×5 ml) and thenwith brine (5 ml). The dichloromethane layer was separated from theaqueous layer, dried over anhydrous sodium sulphate, filtered, andevaporated in vacuo to give the title product as a pale yellow liquid.Purification was attempted by flash chromatography and vacuumdistillation (b.p.=144° C., 3.0 mm of Hg) which afforded the pureproduct as a colorless liquid (527.0 mg, 48%).

Thus obtained compound was characterized by ¹H NMR and mass spec.

¹H NMR (300 MHz, CDCl₃) δ 4.2 (m, 2H), 3.68 (m, 2H), 3.64 (m, 6H), 3.52(m, 2H), 3.36 (s, 3H), 1.62 (m, 1H), 0.99 (m, 2H), 0.84 (m, 2H); MS (ES,MNa⁺) Calcd for C₁₁H₂₀O₅Na 255.11, found 255.1.

EXAMPLE 2

Preparation of Cyclobutanoylglycine (or(cyclobutanecarbonyl-amino)-acetic acid)

Methyl ester glycine hydrochloride (1 eq, 2.39 mmol, 300 mg), pyridine(2 eq, 4.78 mmol, 0.39 ml), was suspended in (5 ml) of dichloromethanefollowed by addition of DMAP (1.5 eq, 218.5 mg) in one portion and thereaction was stirred for 30 min at room temperature. After 30 min,cyclobutanecarbonyl chloride (2 eq, 4.77 mmol, 0.54 ml) was added slowlyand the reaction mixture was stirred for 4 hrs at room temperature. Thesolvent was evaporated in vacuo and the residue extracted with ethylacetate. The ethyl acetate layer was dried and concentrated to dryness.The crude material obtained was purified by flash chromatography toyield pure compound A (358 mg, 87%).

To a solution of A in (6 ml) THF, was added lithium hydroxide (1.1 eq,2.3 mmol, 2.3 ml, 1M) at room temperature and the reaction mixture wasstirred for 1.5 hrs. The reaction mixture was then concentrated in vacuoand acidified to pH=3 with 2N HCl. The crude product was then extractedwith ethyl acetate and purified by recrystallization, using ethylacetate/hexane mixture. The product obtained after recrystallization wasfurther purified by flash chromatography and again recrystallization togive the title compound B as a white solid (196 mg, 59%).

Thus obtained compound was characterized by ¹H NMR and mass spec.

¹HNMR (300 MHz, CD₃OD) δ 3.87 (s, 2H), 3.14 (quintet, 1H), 1.84–2.2 (m,6H); HRMS (ES, MNa⁺) Calcd for C₇H₁₁NO₃Na 180.06311 found 180.06290.

EXAMPLE 3

Preparation of Cyclobutanecarboxylic Acid,2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl Ester

Triethylene glycol monomethyl ether (1.1 eq, 4.64 mmol, 0.74 ml),triethylamine (1.1 eq, 4.64 mmol, 0.65 ml) was taken in a 25 ml roundbottom flask and dichloromethane (3 ml) was added. This mixture wascooled to 0° C. and then cyclobutanecarbonyl chloride (4.22 mmol, 0.5 g,0.48 ml) was added in a dropwise fashion maintaining the temperature at0° C. with constant stirring (Vigorous reaction).

A pink colored solution was observed after some time. An extra 4 ml ofdichoromethane was added to maintain proper stirring (reaction mixturebecomes thick). Stirring was continued for 1 hr at 0° C. The reactionwas monitored by thin layer chromatography and then quenched withsaturated ammonium chloride solution. It was then transferred to aseparatory funnel, washed with 5% sodium bicarbonate (2×5 ml), 1:1hydrochloric acid (2×5 ml) and then with brine (5 ml). Thedichloromethane layer was separated from the aqueous layer, dried overanhydrous sodium sulphate, filtered, and evaporated in vacuo to give thetitle product as a pale yellowish-pink liquid. The liquid was purifiedby flash chromatography and vacuum distillation (b.p.=189° C., 3.0 mm ofHg) to yield the pure product as a colorless liquid (679.6 mg, 65.34%).

The product was characterized by ¹H NMR and mass spec.

¹HNMR (300 MHz, CDCl₃) δ 4.18 (m, 2H), 3.4 (m, 2H), 3.6 (m, 6H), 3.5 (m,2H), 3.32 (s, 3H), 3.1 (quintet, 1H), 2.2 (m, 4H), 1.86 (m, 2H); MS (ES,MNa⁺) Calcd for C₁₂H₂₂O₅Na 269.13, found 269.1.

EXAMPLES 4, 6–16, AND 18–22

Preparation of Cyclopropanecarboxylic Acid and of CyclobutanecarboxylicAcid Derivatives

-   -   where, R=

-   -   -   R′—OH=Corresponding Alcohols        -   Base=Triethylamine or Pyridine        -   Solvent=Dichloromethane

The procedures of Example 1 and Example 3 were followed for preparationcyclopropanecarboxylic acid and of cyclobutanecarboxylic acidderivatives respectively, except that various starting alcohols wereused in place of triethylene glycol monomethyl ether. All obtainedcompounds were characterized by ¹H NMR and mass spec. The results aresummarized in TABLE 1.

EXAMPLE 5

Preparation of Cyclopropanoylalanine

The procedure of Example 2 was followed except that 2.5 equivalents ofpyridine was used instead of 2 equivalents, cyclopropanecarbonylchloride was used in place of cyclobutanecarbonylchloride and methylester alanine hydrochloride was used in palce of methyl ester glycinehydrochloride.

Purified compound B (321 mg, 87%) was characterized by ¹H NMR and massspec.

¹HNMR (300 MHz, CD₃OD) δ 8.25 (br s, 1H), 4.38 (m, 1H), 3.25 (s, 1H),1.64 (m, 1H), 1.39 (dd, 3H), 0.7–0.9 (m, 4H); HRMS (ES, M) Calcd forC₇H₁₂NO₃ 158.08117, found 158.08123.

EXAMPLE 17

Preparation of Cyclopropanecarboxylic Acid 2-isopropoxy-ethyl Ester

2-Isopropoxy-ethanol (1.1 eq, 5.26 mmol, 0.55 g, 0.61 ml), Pyridine (1.1eq, 5.26 mmol, 0.42 g, 0.43 ml) was taken in a 25 ml round bottom flaskand dichloromethane (6 ml) was added. This mixture was cooled to 0° C.and then cyclopropanecarbonyl chloride (4.78 mmol, 0.5 g, 0.43 ml) wasadded in a dropwise fashion maintaining the temperature at 0° C. withconstant stirring.

An orange-yellow colored solution was observed after sometime. An extra2 ml of dichoromethane was added to maintain proper stirring (reactionmixture becomes thick). Stirring was continued for 1 hr at 0° C. Thereaction was monitored by thin layer chromatography and then quenchedwith saturated ammonium chloride solution. It was then transferred to aseparatory funnel, washed with 5% sodium bicarbonate (2×5 ml), 1:1Hydrochloric acid (2×5 ml), and then with brine (5 ml). Thedichloromethane layer was separated from the aqueous layer, dried overanhydrous magnesium sulphate, filtered, and evaporated in vacuo to givethe title product as a pale yellowish-orange liquid. Purification wasattempted by flash chromatography and vacuum distillation (b.p.=33° C.,2.9 mm of Hg) which afforded the pure product as a colorless liquid(630.2 mg, 76.40%).

Characterization of the resulting compound was done by ¹H NMR and massspec.

¹HNMR (400 MHz, CDCl₃) δ 4.2 (m, 2H), 3.6 (m, 3H), 1.65 (m, 1H), 1.15(d, 6H), 1.0 (m, 2H), 0.85 (m, 2H); MS (ES, MNa⁺) Calcd for C₉H₁₆O₃Na195.09, found 195.0

TABLE 1 Starting Starting R′- Molecular Carbonyl YH Example CompoundWeight Chloride compound 1MM054

232.28 P* 2-[2-(2-Methoxy-ethoxy)-ethoxy]-ethanol 2MM055

157.17 B** Methyl esterglycinehydrochloride---(Amino Acid) 3MM056

246.31 B 2-[2-(2-Methoxy-ethoxy)-ethoxy]-ethanol 4MM057

264.31 P 2-(2-Benzyloxy-ethoxy)-ethanol 5MM058

157.17 P Methyl esteralaninehydrochloride(Amino Acid) 6MM059

278.34 B 2-(2-Benzyloxyethoxy)-ethanol 7MM060

244.32 B 2-(2-Butoxy-ethoxy)-ethanol 8MM061

216.27 B 2-(2-ethoxy-ethoxy)-ethanol 9MM062

201.26 P 2-(2-dimethylamino-ethoxy)-ethanol 10MM063

215.29 B 2-(2-dimethylamino-ethoxy)-ethanol 11MM064

258.35 P 2-(2-hexyloxy-ethoxy)-ethanol 12MM065

272.39 B 2-(2-hexyloxy-ethoxy)-ethanol 13MM066

188.23 P 2-(2-methoxy-ethoxy)-ethanol 14MM067

202.25 B 2-(2-methoxy-ethoxy)-ethanol 15MM068

158.20 P 2-(2-ethoxy-ethoxy)-ethanol 16MM069

172.23 B 2-(2-ethoxy-ethoxy)-ethanol 17MM070

172.23 P 2-Isopropoxy-ethanol 18MM071

186.25 B 2-Isopropoxy-ethanol 19MM072

242.27 P 2-(2-Hydroxy-ethoxy)-ethanol 20MM073

270.32 B 2-(2-Hydroxy-ethoxy)-ethanol 21MM074

286.32 P 2-[2-(2-Hydroxy-ethoxy)-ethoxy]-ethanol 22MM075

314.37 B 2-[2-(2-Hydroxy-ethoxy)-ethoxy]-ethanol a. P*Cyclopropanecarbonyl chloride b. B** Cyclobutanecarbonyl chloride

EXAMPLE 23

Glucose oxidation stimulation in untreated myocardium cells andmyocardium cells treated with cyclopropanecarboxylic acid,2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester. Rat hearts were cannulatedfor isolated working heart 60 min aerobic perfusions as described in JPharmacol Exp Ther. 1993; 264:135–144, the entire disclosure of which isincorporated herein by reference.

Male Sprague-Dawley rats (0.3–0.35 kg) were anesthetized withpentobarbital sodium (60 mg/kg IP) and hearts were quickly excised, theaorta was cannulated and a retrograde perfusion at 37° C. was initiatedat a hydrostatic pressure of 60 mm Hg. Hearts were trimmed of excesstissue, and the pulmonary artery and the opening to the left atrium werethen cannulated. After 15 min of Langendorff perfusion, hearts wereswitched to the working mode by clamping the aortic inflow line from theLangendorff reservoir and opening the left atrial inflow line. Theperfusate was delivered from an oxygenator into the left atrium at aconstant preload pressure of 11 mm Hg. Perfusate was ejected fromspontaneously beating hearts into a compliance chamber (containing 1 mlof air) and into the aortic outflow line. The afterload was set at ahydrostatic pressure of 80 mm Hg. All working hearts were perfused withKrebs'-Henseleit solution containing calcium 2.5 mmol/L, glucose 5.5mmol/L, 3% bovine serum albumin (fatty acid free, initial fractionationby heat shock, Sigma), and with 1.2 mmol/L palmitate. Palmitate wasbound to the albumin as described in J Bio Chem. 1992; 267:3825–3831,the entire disclosure of which is incorporated herein by reference.

The perfusate was recirculated, and pH was adjusted to 7.4 by bubblingwith a mixture containing 95% O₂ and 5% CO₂.

Spontaneously beating hearts were used in all perfusions. Heart rate andaortic pressure were measured with a Biopac Systems Inc. blood pressuretransducer connected to the aortic outflow line. Cardiac output andaortic flow were measured with Transonic T206 ultrasonic flow probes inthe preload and afterload lines, respectively. Coronary flow wascalculated as the difference between cardiac output and aortic flow.Cardiac work was calculated as the product of systolic pressure andcardiac output.

Measurement of Glucose Oxidation: Glucose oxidation was measuredsimultaneously by perfusing hearts with [U-¹⁴C] glucose according to theprocedures discussed in Saddik M, et al., J Bio Chem. 1992;267:3825–3831. The entire disclosure of this reference is incorporatedherein by reference. The total myocardial ¹⁴CO₂ production wasdetermined at 10-min intervals from the 60-min aerobic period. Glucoseoxidation rates were determined by quantitative measurement of ¹⁴CO₂production as described in Barbour R L, et al., Biochemistry. 1984;1923:6503–6062. The entire disclosure of this reference is incorporatedherein by reference. ¹⁴CO₂ production for the control group werecompared with the ¹⁴CO₂ production for the group treated withcyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylester. Results are shown on FIG. 1 and TABLE 2.

EXAMPLE 25

Glucose oxidation stimulation in myocardium cells treated withcyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester.

The procedure of Example 23 for was followed except thatcyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl esterin 1 μM, 10 μM, 100 μM and 1000 μM amounts was added to the buffer inplace of the cyclopropanecarboxylic acid,2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester. The results are illustratedin FIG. 2 and TABLE 2.

EXAMPLE 26

Glucose oxidation stimulation in myocardium cells treated withcyclopropanecarboxylic acid, 2-isopropoxy ethyl ester.

The procedure of Example 23 was followed except thatcyclopropanecarboxylic acid, 2-isopropoxy-ethyl ester in 1 μM, 10 μM,100 μM and 1000 μM amounts was added to the buffer in place of thecyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxyl]-ethylester. The results are illustrated in FIG. 3 and TABLE 2.

EXAMPLES 24, 27–41 AND 43

Glucose oxidation stimulation in myocardium cells treated with variouscyclopropanecarboxylic acid and cyclobutanecarboxylic acid derivatives.

The procedure of Example 23 was followed except that variouscyclobutanecarboxylic acid derivatives, cyclopropanecarboxylic acidderivatives and cyclobutanecarboxylic acid in the amounts of 100 μM or1000 μM was added to the buffer in place of the cyclopropanecarboxylicacid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester. The results areillustrated in TABLE 2.

EXAMPLE 42

Glucose oxidation stimulation in myocardium cells treated withcyclopropanecarboxylic acid.

The procedure of Example 23 was followed except thatcyclobutanecarboxylic acid the amounts of 0.001 μM, 0.01 μM, 01 μM, 1μM, 10 μM, and 100 μM was added to the buffer in place of thecyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylester. The results are illustrated in FIG. 4 and TABLE 2.

TABLE 2 Screening Glucose Concentration Oxidation Example Compound (μM)(% above control) 23MM054

100 102% 24MM055

1000 μM  58% 25MM056.

100 μM 54% 26MM057

100 μM 104% 27MM058

1000 μM  40% 28MM059

100 μM 68% 29MM060

100 μM 65% 30MM062

100 μM 77% 31MM063

100 μM 41% 32MM064

100 μM 83% 33MM065

100 μM 0% 34MM066

100 μM 20% 35MM067

100 μM 50% 36MM068

100 μM 416% 37MM069

100 μM 162% 38MM070

100 μM 208% 40MM071

100 μM 97% 41MM072

100 μM 97% 42MM001

1000 μM  121% 43MM002

1000 μM  239%

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.

1. A sterile aqueous solution, dispersion or suspension of an injectablepharmaceutical composition comprising a physiologically acceptablecarrier and a glucose utilization increasing amount of at least onecompound represented by Formula (I)

W is C₁–C₆ alkyl, halogen, or aryl; Cyc is C₃ or C₄ cycloalkyl; p is 0–3for Cyc being C₄ cycloalkyl, or p=0–2 for Cyc being C₃ cycloalkyl; Y isO, S, or NR , where R═H, alkyl or aryl; X is O, S, NR, or CR³R⁴; Z is H,alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl; R¹ is H, alkyl, aryl;R² is H, alkyl, aryl or ═O; R³ and R⁴ are, independently, H, alkyl oraryl; and n is an integer from 1 to 10; or a pharmaceutically acceptablesalt, ester or prodrug thereof; and a pharmaceutically acceptablecarrier, diluent, excipient or mixtures thereof.
 2. The pharmaceuticalcomposition as claimed in claim 1, wherein said compound is representedby Formula (I), and wherein p=0; Y is O; X is N or O; R¹, R², R³ and R⁴are hydrogens; n is 1–4; and Z is lower alkyl, cycloalkyl or phenyl. 3.The pharmaceutical composition as claimed in claim 1, wherein saidcompound is represented by the Formula (I), and wherein p=0; Y is N; Xis O; R¹, R², R³ and R⁴ are hydrogens; n is 1 or 2; and Z is hydrogen.4. The pharmaceutical compositions as claimed in claim 1, wherein saidcomposition is in the form of sterile suspensions or solutions.
 5. Thepharmaceutical composition according to claim 1, wherein said at leastone compound is selected from the group consisting ofcyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylester; cyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylester; cyclopropanecarboxylic acid, 2-(2-benzyloxy-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-butoxy-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;cyclopropanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester;cyclopropanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester;cyclopropanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;cyclopropanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;cyclopropanecarboxylic acid 2-isopropoxy-ethyl ester; andcyclobutanecarboxylic acid 2-isopropoxy-ethyl ester.
 6. A method forincreasing glucose utilization in a cell, tissue or organ of a warmblooded animal comprising treating said cell, tissue or organ withglucose utilization effective amount of at least one compoundrepresented by Formula (I)

wherein W is C₁–C₆ alkyl, halogen, or aryl; Cyc is C₃ or C₄ cycloalkyl;p is an integer from 0 to 3 when Cyc is C₄ cycloalkyl, or p is aninteger from 0 to 2 when Cyc is C₃ cycloalkyl; Y is O, S, or NR, where Ris H, alkyl, or aryl; X is O, S, NR, or CR³R⁴; Z is H, alkyl,cycloalkyl, aryl or (cyclo)alkylcarbonyl; R¹ is H, alkyl or aryl; R² isH, alkyl, aryl or O; R³ and R⁴ are, independently, H, alkyl or aryl; andn is an integer from 1 to 10; or a pharmaceutically acceptable salt,ester or prodrug thereof.
 7. The method as claimed in claim 6, whereinsaid compound is represented by Formula (I), and wherein p=0; Y is O; Xis N or O; R¹, R², R³ and R⁴ are hydrogens; n is 1–4; and Z is loweralkyl, cycloalkyl or phenyl.
 8. The method as claimed in claim 6,wherein said compound is represented by Formula (I), and wherein p=0; Yis N; X is O; R¹, R², R³ and R⁴ are hydrogens; n is 1 or 2; and Z ishydrogen.
 9. The method as claimed in claim 6, wherein said organ isheart.
 10. The method according to claim 6, wherein said cell is amyocardial cell.
 11. The method according to claim 6, wherein said atleast one compound is selected from the group consisting ofcyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylester; cyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylester; cyclopropanecarboxylic acid, 2-(2-benzyloxy-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-butoxy-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;cyclopropanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester;cyclopropanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester;cyclopropanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;cyclopropanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;cyclopropanecarboxylic acid 2-isopropoxy-ethyl ester; andcyclobutanecarboxylic acid 2-isopropoxy-ethyl ester.
 12. A method fortreatment of physiological conditions or disorders treatable byincreasing glucose utilization comprising: administering to a patient inneed of such treatment, effective amount to increase glucose utilizationof a pharmaceutical composition comprising at least one compoundrepresented by Formula (I)

wherein W is C₁–C₆ alkyl, halogen, or aryl; Cyc is C₃ or C₄ cycloalkyl;p is an integer from 0 to 3 when Cyc C₄ cycloalkyl, or p is an integerfrom 0 to 2 when Cyc is C₃ cycloalkyl; Y is O, S, or NR, where R is H,alkyl, or aryl; X is O, S, NR, or CR³R⁴; Z is H, alkyl, cycloalkyl, arylor (cyclo)alkylcarbonyl; R¹ is H, alkyl, or aryl; R² is H, alkyl aryl orO; R³ and R⁴ are, independently, H, alkyl or aryl; and n is an integerfrom 1 to 10; or a pharmaceutically acceptable salt, ester or prodrugthereof.
 13. The method as claimed in claim 12, wherein said disorder orcondition is ischemic/reperfusion injury, post myocardial infarction,angina, heart failure, a cardiomyopathy, peripheral vascular disease,diabetes, and lactic acidosis, or symptoms or side effects associatedwith open heart surgery, bypass surgery, or heart transplant.
 14. Themethod as claimed in claim 13, wherein said disorder or condition isischemic/reperfusion injury.
 15. The method as claimed in claim 12,wherein said compound is represented by the Formula (I), and whereinp=0; Y is O; X is N or O; R¹, R², R³ and R⁴ are hydrogens; n is 1–4; andZ is lower alkyl, cycloalkyl or phenyl.
 16. The method as claimed inclaim 12, wherein said compound is represented by the Formula (I), andwherein p=0; Y is N; X is O; R¹, R², R³ and R⁴ are hydrogens; n is 1 or2; and Z is hydrogen.
 17. The method according to claim 12, wherein saidat least one compound is selected from the group consisting ofcyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylester; cyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylester; cyclopropanecarboxylic acid, 2-(2-benzyloxy-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-butoxy-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;cyclopropanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester;cyclopropanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester;cyclopropanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;cyclopropanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;cyclopropanecarboxylic acid 2-isopropoxy-ethyl ester; andcyclobutanecarboxylic acid 2-isopropoxy-ethyl ester.
 18. A kitcontaining a pharmaceutical composition as claimed in claim
 1. 19. Thekit as claimed in claim 18, wherein said kit comprises a label orpackaging insert containing instructions for use, in vitro, in vivo, orex vivo, of components of said kit.
 20. A composition according to claim1 wherein Y is O, X is NR or O, n is 1 to 4, p is 0; R¹, R², R³ and R⁴are hydrogen and Z is cycloalkylcarbonyl.
 21. A composition according toclaim 20 wherein n is
 3. 22. A composition according to claim 21 whereinCyc is C₃ cycloalkyl.
 23. A composition according to claim 22 wherein Zis cyclopropylcarbonyl.
 24. An oral pharmaceutical composition fortreatment of physiological conditions or disorders treatable byincreasing glucose utilization in unit dosage form comprising a glucoseutilization increasing amount of at least one compound represented byFormula (I):

wherein W is C₁–C₆ alkyl, halogen, or aryl; Cyc is C₃ or C₄ cycloalkyl;p is an integer from 0 to 3 when Cyc C₄ cycloalkyl, or p is 0 to 2 whenCys is C₃ cycloalkyl; Y is O, S, or NR, where R is H, alkyl, or aryl; Xis O, S, NR, or CR³R⁴; Z is H, alkyl, cycloalkyl, aryl or(cyclo)alkylcarbonyl; R¹ is H, alkyl, or aryl; R² is H, alkyl aryl or O;R³ and R⁴ are, independently, H, alkyl or aryl; and n is an integer from1 to 10; or a pharmaceutically acceptable salt, ester or prodrugthereof; and a pharmaceutically acceptable carrier, diluent, excipientor mixtures thereof.
 25. The pharmaceutical composition as claimed inclaim 24, wherein said compound is represented by Formula (I), andwherein p=0; Y is O; X is N or O; R¹, R², R³ and R⁴ are hydrogens; n is1–4; and Z is lower alkyl, cycloalkyl or phenyl.
 26. The pharmaceuticalcomposition as claimed in claim 24, wherein said compound is representedby the Formula (I), and wherein p=O; Y is N; X is O; R¹, R², R³ and R⁴are hydrogens; n is 1 or 2; and Z is hydrogen.
 27. The pharmaceuticalcompositions as claimed in claim 24, wherein said composition is in theform of tablets, pills, or capsules.
 28. the pharmaceutical compositionaccording to claim 24, wherein said at least one compound is selectedfrom the group consisting of cyclopropanecarboxylic acid,2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester; cyclobutanecarboxylic acid,2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester; cyclopropanecarboxylicacid, 2-(2-benzyloxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid2-(2-benzyloxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid2-(2-butoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid2-(2-ethoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid2-(2-dimethylamino-ethoxy)-ethyl ester; cyclobutanecarboxylic acid2-(2-dimethylamino-ethoxy)-ethyl ester; cyclopropanecarboxylic acid2-(2-hexyloxy-ethoxy)-ethoxy)-ethyl ester; cyclobutanecarboxylic acid2-(2-hexyloxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid2-(2-methoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid2-(2-methoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid2-(2-ethoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid2-(2-ethoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid2-isopropoxy-ethyl ester; and cyclobutanecarboxylic acid2-isopropoxy-ethyl ester.
 29. A kit containing a pharmaceuticalcomposition as claimed in claim
 24. 30. The kit as claimed in claim 29,wherein said kit comprises a label or packaging insert containinginstructions for use, in vitro, in vivo, or ex vivo, of components ofsaid kit.
 31. A composition according to claim 24 wherein Y is O, X isNR or O, n is 1 to 4, p is 0; R¹, R², R³ and R⁴ are hydrogen; and Z iscyclopropylcarbonyl.
 32. A composition according to claim 31 wherein nis
 3. 33. A composition according to claim 32 wherein Cyc is C₃cycloalkyl.
 34. A composition according to claim 33 wherein Z iscyclopropylcarbonyl.